Alzheimer's disease (AD) is a devastating neurological disorder and the most common cause of dementia. The genetics of this disorder suggest that multiple genes are involved. To date, mutations in four genes have been found to be associated with Alzheimer's disease phenotypes including the Amyloid Precursor Protein (APP) gene on chromosome 21 (Citron, M. et al., Nature 360, 672-674 (1992); Suzuki, N. et al., Science 264, 1336-1340 (1994)), the Apolipoprotein-E (APOE) gene on chromosome 19 (Corder, E. H. et al., Science 261, 921-923 (1993); Corder, E. H. et al., Nat. Genet. 7, 180-184 (1994); Strittmatter, W. J. et al., Proc. Natl. Acad. Sci. U.S.A. 90, 1977-81 (1993)), the Presenilin-1 (PS-1) gene on chromosome 14 (Sherrington, R. et al., Nature 375, 754-760 (1995)) and the Presenilin-2 (PS-2) gene on chromosome 1 (Levy-Lahad, E.et al., Science 269, 973-977 (1995)). An unknown gene on chromosome 12 appears to associate with a large percentage of late-onset AD patients (Stephanson, J. J Am. Med. Asoc. 277, 775 (1997)). The majority of familial Alzheimer's disease cases are associated with mutations in the PS-1. To date, over 30 independent mutations in the PS-1 gene have been described in unrelated Alzheimer's families displaying an early-age-of-onset phenotype. Most of these mutations are missense mutations that result in single amino acid changes (Wasco, W. et al., Nat. med. 1, 848 (1995); Alzheimer's Disease Collaborative Group, Nat. Genet. 11, 219-222 (1995); Campion, D. et al., Hum. Mol. Genet. 4, 2373-2377 (1995); Cruts, M.et al., Hum. Mol. Genet. 4, 2363-2371 (1995); Boteva, K. et al., Lancet 347, 130-131 (1996); Rossor, M. et al., Lancet 347, 1560 (1996); Kamino, K. et al., Neurosci. Let. 208, 195-198 (1996)).
Deletions found in Exons 4 and 9 cause additional mutations as do several truncations of the RNA transcripts arising by differential splicing (Perez-Tur, J. et al., Neuroreport. 7, 297-301 (1995).). Although clustering of these mutations within the protein suggests the location of functionally important domains, the exact function of Presenilin proteins is a matter of active investigation.
One approach to find gene function is to study the regulation of PS-1 gene expression. Using in situ hybridization, we and others demonstrate that PS-1 mRNA is most highly expressed in neurons of the brain (Koracs, D. M. et al., Nat. Med. 2, 224-229 (1996)). Immunohistochemistry revealed that the PS-1 protein was abundant in neurons, but was also associated with amyloid plaques and some glial cell types (Scheuner, D. et al., Nat. Med. 2, 864-870 (1996); Lah, J. et al., J. Neurosci. 17, 1971-1980 (1997)). In contrast, Sherrington et al. reported that PS-1 mRNA is widely expressed in a variety of organs throughout the body (Nature 375, 754-760 (1995)). This raises the question as to why mutations in the PS-1 gene product appear to confer a disease state in familial Alzheimer's patients without apparent effect on their peripheral organs. The situation is further compounded because PS-1 mRNA and protein levels from FAD patients and age-matched healthy controls have not been reported, leaving open the possibility that aberrant regulation of PS-1 gene expression further contributes to the disease state.
Mutations in the PS-1 gene's promoter and non-protein encoding regions are not known and reports on the gene's wild-type sequence are lacking. Similarly, no functional analysis of the gene's ability to promote transcription have been reported. Combined with recent reports that PS-1 knockout mice are embryonic lethal ( Shen, J. et al., Cell 89, 629-639 (1997)), knowledge of the PS-1 gene sequence and its transcriptional regulation should be important clues that help to identify PS-1 function in both noon and diseased states.